Systems and methods for increasing convective clearance of undesired particles in a microfluidic device

ABSTRACT

A microfluidic device for increasing convective clearance of particles from a fluid is provided. A network of first channels can be separated from a network of second channels by a first membrane. The network of first channels can also be separated from a network of third channels by a second membrane. Fluid containing an analyte can be introduced in the network of first channels. Infusate can be introduced into the network of second channels, and waste-collecting fluid can be introduced into the network of third channels. A pressure gradient can be applied in a direction perpendicular to the direction of fluid flow in the network of first channels, such that the analyte is transported from the network of first channels into the network of third channels through the second membrane.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. patent application Ser. No.13/739,685, filed on Jan. 11, 2013 and entitled “SYSTEMS AND METHODS FORINCREASING CONVECTIVE CLEARANCE OF UNDESIRED PARTICLES IN A MICROFLUIDICDEVICE,” which is hereby incorporated by reference in its entirety.

BACKGROUND

A dialysis device contains a series of fluid channels separated by apermeable membrane. Convective clearance of solutes from blood in thedevice is determined by the transmembrane pressure in the device.Typically, the fluid in adjacent channels flows in opposite directionsand the channels have a non-linear fluid volume profile along theirlengths. Increasing the convective clearance requires decreasing thefluid volume in the channel carrying blood, which can result in anunsafe hematocrit level in the channel. Therefore, it is desirable toincrease the amount of convective clearance within a compact dialysisdevice while maintaining safe hematocrit levels throughout the bloodchannel.

SUMMARY OF THE INVENTION

Aspects and implementations of the present disclosure are directed to adevice for increasing convective transport of solutes in blood within adialysis system.

At least one aspect is directed to a microfluidic device. Themicrofluidic device includes a first network of channels having aplurality of First Channels. Each First Channel has a height in therange of about 50 microns to about 500 microns, a width in the range ofabout 50 microns to about 1.5 millimeters, and a length in the range ofabout 3 centimeters to about 20 centimeters. The microfluidic deviceincludes a second network of channels having at least one Second Channelcomplementary to one or more of the First Channels. The microfluidicdevice includes a first filtration membrane separating the one or moreFirst Channels from the at least one Second Channel. The microfluidicdevice includes a third network of channels having at least one ThirdChannel complementary to one or more of the First Channels. Themicrofluidic device includes a second filtration membrane separating theone or more First Channels from the at least one Third Channel.

In some implementations, the microfluidic device includes a fluidintroduction device configured to flow fluid in the at least one SecondChannel. The fluid can be flowed in a direction perpendicular to adirection of fluid flow in the one or more First Channels, such thatfluid flows from the at least one Second Channel into the one or moreFirst Channels and from the one or more First Channels into the at leastone Third Channel.

In some implementations, the microfluidic device can include at leastone structural support within at least one of the First, Second, orThird Channels. The structural support can be configured to limit thedeformation of the first or second membrane towards the one or moreFirst Channels or the at least one Second Channel. The structuralsupport can be a porous mesh made from ceramic, carbon, or polymer. Thestructural support can also be a post or ridge placed within the one ormore First Channels, the at least one Second Channel, or the at leastone Third Channel.

In some implementations, the one or more First Channels of themicrofluidic device are defined in part by a substantially planarsubstrate. The at least one Second Channel and the at least one ThirdChannel can be configured to allow fluid to flow in a directionperpendicular to the plane of the substrate. In some implementations,the microfluidic device can be configured such that the volume of fluidin the one or more First Channels is substantially constant along itslength.

In some implementations, the pore size of the second membrane isselected to allow clearance of particles with a molecular weight of nomore than about 60 kDa. The one or more First Channels can be configuredto receive a net infusion of fluid from the at least one Second Channelthrough the first membrane and can be further configured to provide anet outflow of fluid into the at least one Third Channel through thesecond membrane. In some implementations, the device is configured suchthat a hematocrit profile in the one or more First Channels isselectably controllable by an operator of the device when blood isflowed through the one or more First Channels.

In some implementations, the microfluidic device is configured such thathematocrit is substantially constant throughout the one or more FirstChannels when blood is transported through the one or more FirstChannels. In some implementations, the one or more First Channels areconfigured such that fluid flow in the one or more First Channels issubstantially laminar. In some implementations, the one or more FirstChannels are configured to maintain wall shear rates in the range of300-3000 inverse seconds when blood is transported through the one ormore First Channels. In some implementations, the microfluidic deviceincludes an anticoagulant coating on the inner surfaces of the one ormore First Channels.

At least one aspect is directed to a method for filtering a first liquidcontaining an analyte to provide a filtered liquid containing lessanalyte than the first liquid. The method can include introducing thefirst liquid into an inlet of one or more First Channels, each FirstChannel having a height in the range of about 50 microns to about 500microns, a width in the range of about 50 microns to about 900 microns,and a length in the range of about 3 centimeters to about 20centimeters. The method can include introducing an infusate into atleast one Second Channel complementary to the one or more First Channelsin a direction perpendicular to the direction of fluid flow in the oneor more First Channels, such that at least some of the infusate flowsfrom the at least one Second Channel through a first membrane and intothe one or more First Channels. The method can include introducingwaste-collecting fluid into at least one Third Channel complementary tothe one or more First Channels such that at least some of the analyte ofthe first liquid is transported through a second membrane into the atleast one Third Channel. The method can include collecting the filteredsolution from an outlet of one or more of the First Channels.

In some implementations, introducing the first liquid includesintroducing blood. The blood can be extracted from a patient and canfiltered blood can be returned to the patient. The blood and theinfusate can be introduced such that hematocrit of the blood issubstantially constant throughout the one or more First Channels. Theblood can be introduced such that a fluid shear rate in the one or moreFirst Channels is within a range of about 300 inverse seconds to about3000 inverse seconds. The one or more First Channels can include ananticoagulant coating on its inner walls.

In some implementations, the first liquid and the infusate can beintroduced such that the volume of fluid in each of the one or moreFirst Channels is substantially constant along its length. The firstliquid and the infusate can be introduced such that fluid flow in theone or more First Channels is substantially laminar. In someimplementations, the first liquid and the infusate can be introducedsuch that a pressure in the at least one Second Channel is greater thana pressure in the one or more First Channels, and the pressure in theone or more First Channels is greater than a pressure in the at leastone Third Channel.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are not intended to be drawn to scale. Likereference numbers and designations in the various drawings indicate likeelements. For purposes of clarity, not every component may be labeled inevery drawing.

FIG. 1A is a cross-sectional view of a first microfluidic convectiveclearance device for use in hemofiltration, according to an illustrativeimplementation.

FIG. 1B is a cross-sectional view of a second microfluidic convectiveclearance device for use in hemofiltration, according to an illustrativeimplementation.

FIG. 1C is a cross-sectional view of a third microfluidic convectiveclearance device for use in hemofiltration, according to an illustrativeimplementation.

FIGS. 2A-2H depict the device of FIG. 1A at various points in themanufacturing process, according to an illustrative implementation.

FIG. 3 is a block diagram of a control system that can be used with thedevices of FIGS. 1A-1C, according to an illustrative implementation.

FIG. 4 is a flow diagram of a method for filtering liquid containing ananalyte, according to an illustrative implementation.

DESCRIPTION OF CERTAIN ILLUSTRATIVE IMPLEMENTATIONS

Following below are more detailed descriptions of various conceptsrelated to, and implementations of, a device for increasing convectivetransport of solutes in blood within a dialysis system. The variousconcepts introduced above and discussed in greater detail below may beimplemented in any of numerous ways, as the described concepts are notlimited to any particular manner of implementation. Examples of specificimplementations and applications are provided primarily for illustrativepurposes.

FIG. 1A is a cross-sectional view of a first microfluidic convectiveclearance device 100 a for use in hemofiltration The convectiveclearance device 100 a includes a blood channel 102 a, an infusatechannel 104 a, and a waste channel 106 a. A first membrane 108 aseparates the blood channel 102 a from the infusate channel 104 a, and asecond membrane 110 a separates the blood channel 102 a from the wastechannel 106 a. The infusate channel 104 a and the waste channel 106 aalso include structural supports 112 a.

The blood channel 102 a has a depth in the range of about 50 microns toabout 500 microns, a width in the range of about 50 microns to about 900microns, and a length in the range of about 3 centimeters to about 20centimeters. The infusate channel 104 a is defined by an infusatesubstrate 114 a and the waste channel 106 a is defined by a wastesubstrate 116 a. The substrates 114 a and 116 a can be made from apolystyrene, polycarbonate, polyimide, polysulfone, polyethersulfone,acrylic, or cyclic olefin copolymer (COC), biodegradable polyesters,such as polycaprolactone (PCL), soft elastomers such as polyglycerolsebacate (PGS), or other thermoplastics. The substrates mayalternatively be made of polydimethylsiloxane (PDMS),poly(N-isopropylacrylamide), or nanotubes or nanowires formed from, forexample, carbon or zinc oxide.

The upper and lower walls of the blood channel 102 a are defined by themembranes 110 a and 108 a, respectively. In some implementations, theside walls of the blood channel can be made from a substrate materialsimilar to the substrates 114 a and 116 a. The blood channel 102 a canbe coated with cytophilic or cytophobic materials to promote or preventthe growth of cells, such as vascular endothelial cells, in thechannels. The blood channel 102 a may also be coated with ananticoagulant to help prevent clotting of the blood. In someimplementations, the anticoagulant is applied to the substrate walls ofthe blood channel 102 a, but not to the walls defined by the membranes108 a and 110 a.

The convective clearance device 100 a is designed for use inhemofiltration. The blood channel 102 a, the infusate channel 104 a, andthe waste channel 106 a are configured such that a relatively largesurface area of the fluid flowing through the channels is exposed to themembranes 108 a and 110 a. In some implementations, the channels 100 a,104 a, and 106 a can have rectangular cross-sections, with a relativelylarge fluid interface at the membranes 108 a and 110 a, to promote fluidcommunication between the blood channel 102 a, the infusate channel 104a, and the waste channel 106 a. The channels 102 a, 104 a, and 106 a canalternatively have semicircular cross sections. In otherimplementations, the channels 102 a, 104 a, and 106 a may have any othertype of cross section, such as a substantially rectangular cross-sectionwith rounded corners, or an irregularly shaped cross-section.

Blood is introduced into an inlet 118 a of the blood channel 102 a andflows along the length of the blood channel 102 a in the directionindicated by arrow 120 a. Infusate (e.g., saline) is simultaneouslyintroduced into the infusate channel 104 a through inlets 122 a. Atransverse pressure is applied to the infusate channel 104 a and thewaste channel 106 a, causing fluid in these channels to flow in thedirections indicated by the arrows 124 a and 126 a, respectively. Asblood flows through the blood channel 102 a, the transverse pressuregradient causes an infusion of infusate to flow from the infusatechannel 104 a, through the membrane 108 a, and into the blood channel102 a. The infusion of infusate increases the total amount of fluid inthe blood channel 102 a, resulting in an increased pressure in the bloodchannel 102 a. Therefore, fluid from the blood channel 102 a, includingplasma, urea, and other waste particles, such as particle 109 a, isforced into the waste channel 106 a through the membrane 110 a. Cleansedblood can then be collected from an outlet 128 a of the blood channel102 a. Waste-collecting fluid passes out of the convective clearancedevice 100 a through outlets 130 a in the waste collecting channel, andcan then be filtered and recirculated back to the inlets 122 a of theinfusate channel 104 a. Blood and infusate can be introduced in such away as to maintain substantially laminar flow in the blood channel 102a. In some implementations, the infusate channel 104 a and the wastechannel 106 a can be reservoirs or fluid baths whose volume issignificantly larger than the volume of the blood channel 102 a.

The membrane 110 a can be configured to allow clearance of particleshaving a molecular weight of less than about 60 kDa. Larger particlesexemplified by particle 132 a, such as blood cells, can remain withinthe blood channel. The membrane 108 a can be identical to the membrane110 a. However, in some implementations, the membrane 108 a can havepore sizes that are significantly smaller than the pore sizes of themembrane 110 a, because it is only necessary to allow fresh infusate topass through the membrane 108 a. For example, smaller pore sizes may beselected to prevent the introduction of impurities into the bloodchannel 102 a while still allowing infusate to flow into the bloodchannel 102 a. In other implementations, desirable solutes may beintroduced into the infusate channel 104 a, and the membrane 108 a canbe configured to allow the desirable solutes to pass into the bloodchannel 102 a. The membrane 108 a can be made from an impermeablematerial into which pores have been fashioned, for example by a laseretching process. Alternatively, the membrane 108 a can be constructedfrom a naturally porous material.

The pressure gradient indicated by the arrows 124 a and 126 a issubstantially constant throughout the lengths of the infusate channel104 a and the waste channel 106 a. For example, substantially constantpressure can be achieved by positioning a number of inlets 122 a alongthe length of the infusate channel 104 a. Similarly, a number of outlets130 a can be positioned along the length of the waste-collecting channel106 a. This allows the blood channel 102 a to experience a simultaneousinfusion of fluid from the infusate channel 104 a and outflow of fluidto the waste channel 106 a, which results in a substantially constantvolume of blood along the length of the blood channel 102 a. Bycontrast, in typical hemodialysis devices, forward filtration occursalong a portion of the length of the device, and back filtration occursalong a separate portion of the device, resulting in a varying fluidvolume profile along the length of the device. Achieving increasedconvective clearance in these types of devices requires a largervariance of the volume of blood along the length of the device, whichcan lead to unsafe hematocrit levels.

Hematocrit in the blood channel 102 a is preferably maintained within anacceptable range in order to ensure blood health. The substantiallyconstant volume of fluid maintained in the blood channel 102 a causes asubstantially constant hematocrit level in the blood channel 102 a.Therefore the amount of convective clearance achieved in the convectiveclearance device 100 a can be increased without significantly increasingthe risk of unsafe hematocrit levels. In some implementations, theamount of convective clearance is proportional to the magnitude of thetransverse pressure gradient indicated by arrows 124 a and 126 a. Asdiscussed above, increasing the infusion of fluid from the infusatechannel 104 a to the blood channel 102 a results in an increased outflowof fluid form the blood channel 102 a to the waste channel 106 a, whilepreserving the volume of fluid in the blood channel 102 a. Otherhemodialysis devices typically require increased channel lengths andincreased residence time of fluid in the channels in order to increasethe amount of convective clearance. The convective clearance device 100a can therefore be used to achieve significantly higher levels ofconvective clearance without a need for increasing the overall size ofthe convective clearance device 100 a.

The transverse pressure gradient may expose the membranes 108 a and 110a to stresses that can cause the membrane 108 a to deform towards theblood channel 102 a and can cause the membrane 110 a to deform towardsthe waste channel 106 a. To prevent significant deformation of themembranes 108 a and 110 a, the infusate channel 104 a and thewaste-collecting channel 106 a can include structural supports 112 a.The structural supports 112 a can span the width of the infusate channel104 a and the waste-collecting channel 106 a, and can be attached to themembranes 108 a and 110 a to hold them in place against the force of thefluid pressure gradient indicated by arrows 124 a and 126 a. In otherimplementations, the structural supports 112 a can substantially fillthe volume of the infusate channel 104 a and the blood channel 106 a toprovide rigidity to the channels 104 a and 106 a and reduce deformationof the membranes 108 a and 110 a. For example, the structural supports112 a can be porous mesh structures made from ceramic, carbon, polymer,or other materials. The structural supports 112 a can also be posts orridges inserted into the blood channel 102 a, the infusate channel 104a, or the waste-collecting channel 106 a. To prevent the obstruction offluid flow in the infusate channel 104 a and the waste-collectingchannel 106 a, the structural supports 112 a can be selected to havepore sizes that are larger than the pore sizes of the membranes 108 aand 110 a, so that the clearance of particles from the fluids iscontrolled only by the pore sizes of the membranes 108 a and 110 a.

In some implementations, a microfluidic convective clearance devicesimilar to the device 100 a can be configured such that only a portionof the fluid in the infusate channel and waste channel flowsperpendicular to the flow of fluid in the blood channel, while theremaining portion of fluid in the infusate channel and waste channelflows parallel to the flow of fluid in the blood channel. An example ofsuch a device is shown in FIG. 1B

FIG. 1B is a cross-sectional view of a second microfluidic convectiveclearance device 100 b for use in hemofiltration, according to anillustrative implementation. The device 100 b includes many of thefeatures of the device 100 a shown in FIG. 1A. For example, the device100 b includes a blood channel 102 b, an infusate channel 104 b, and awaste-collecting channel 106 b. The channels are defined by walls madefrom substrate materials 114 b and 116 b and membranes 108 b and 110 b,and can include structural supports 112 b. Fluid can be introduced intoan inlet 140 b of the infusate channel 104 b. The pressure in theinfusate channel 104 b causes some of the fluid to pass through themembrane 108 b and into the blood channel 102 b, in the direction shownby the arrow 127 b. The remaining portion of the fluid in the infusatechannel 104 b can travel parallel to the blood channel 102 b along thelength of the channel 104 b, as shown by the arrow 125 b, and can becollected at an outlet 142 b.

The infusion of fluid from the infusate channel 104 b into the bloodchannel 102 b increases the pressure in the blood channel 102 b, causingsome of the fluid in the blood channel 102 b to pass into thewaste-collecting channel 106 b through the membrane 110 b, in thedirection shown by the arrow 129 b. Undesired particles, such asparticle 109 b, can also pass through the membrane 110 b into thewaste-collecting channel 106 b. In some implementations, additionalwaste-collecting fluid can be introduced at an inlet 146 b of thewaste-collecting channel 106 b, causing fluid within thewaste-collecting channel 106 b to flow in the direction shown by arrow131 b. Waste-collecting fluid can be collected from the outlet 144 b,and purified blood can be collected from the outlet 128 b as the bloodflows along the blood channel 102 b in the direction shown by the arrow120 b. In some other implementations, the waste-collecting fluid can beintroduced such that the fluid in the waste-collecting channel flows ina direction opposite the direction shown by arrow 131 b.

FIG. 1C is a cross-sectional view of a third microfluidic convectiveclearance device 100 c for use in hemofiltration, according to anillustrative implementation. The device 100 c includes many of thefeatures of the device 100 a shown in FIG. 1A. For example, the device100 c includes a blood channel 102 c, an infusate channel 104 c, and awaste-collecting channel 106 c. The channels are defined by walls madefrom substrate materials 114 c and 116 c and membranes 108 c and 110 c,and can include structural supports 112 c. Unlike the device 100 b ofFIG. 1B in which the an infusate channel 104 b and a waste collectingchannel 106 b run parallel to the blood channel 102 b, the infusatechannel 104 c and waste-collecting channel 106 c of the device 100 c areoriented perpendicular to the blood channel 102 c.

Fluid can be introduced into an inlet of the infusate channel 104 c inthe direction shown by the vector 134 c (i.e, directed into the page).The pressure in the infusate channel 104 c causes some of the fluid topass through the membrane 108 c and into the blood channel 102 c, in thedirection shown by the arrow 150 c. The remaining portion of the fluidin the infusate channel 104 c can travel along the length of the channel104 c, in the direction of the vector 134 c, and can be collected at anoutlet.

The infusion of fluid from the infusate channel 104 c into the bloodchannel 102 c increases the pressure in the blood channel 102 c, causingsome of the fluid in the blood channel 102 c to pass into thewaste-collecting channel 106 c through the membrane 110 c, in thedirection shown by the arrow 152 c. Undesired particles, such asparticle 109 c, can also pass through the membrane 110 c into thewaste-collecting channel 106 c. In some implementations, additionalwaste-collecting fluid can be introduced at an inlet of thewaste-collecting channel 106 c, causing fluid within thewaste-collecting channel 106 c to flow in the direction shown by vector136 c (i.e., out of the page). Waste-collecting fluid can be collectedfrom an outlet of the waste-collecting channel, and purified blood canbe collected from the outlet 128 c of the blood channel 102 c as theblood travels along the blood channel 102 c in the direction shown byarrow 120 c. In some other implementations, the waste-collecting fluidcan be introduced such that the fluid in the waste-collecting channelflows in a direction opposite the direction shown by vector 136 c (i.e.,parallel to the direction of fluid flow in the infusate channel 104 c.

FIGS. 2A-2F depict the device of FIG. 1A at various points in themanufacturing process. FIG. 2A shows a rectangular block of substratematerial 216. The substrate material can be used to form either theinfusate channel or the waste-collecting channel of FIG. 1A, as both ofthese channels are very similar. Therefore, the processes discussed inconnection with the manufacture of either channel will also be useful inthe manufacture of the other. The substrate material 216 can be any ofthe materials described above in connection with the substrates used inthe device of FIG. 1A, such as thermoplastics, biodegradable polyesters,or nanotubes or nanowires formed from, for example, carbon or zincoxide. The substrate material 216 can be a solid block whose dimensionsare selected to provide sufficient volume to form the infusate channelor waste collecting channel of FIG. 1A.

FIG. 2B shows a cross-sectional view of the substrate 216 of FIG. 2Aafter it has been hollowed out to form a channel 206. For example, thechannel 206 can be used as the infusate channel or the waste-collectingchannel of FIG. 1A. The channel 206 can be created in the substrate 216by any method of material removal, such as an etching or millingprocess. The result is the hollow channel 216 suitable for carryinginfusate or waste-collecting fluid, surrounded on three sides by thesubstrate material 216. The fourth side of the channel will be formed bya membrane, so the substrate material 216 is completely removed fromthis side.

FIG. 2C shows a cross-sectional view of the substrate 216 and thechannel 206. Also shown are openings 230 leading into the channel 206.The openings 230 can be used as the infusate inlets or waste fluidoutlets described in FIG. 1A. In some implementations, the openings 230are positioned evenly across the surface of the substrate 216, tofacilitate an even pressure gradient along the length of the channel206. Although five openings 216 are shown in FIG. 2C, any number ofopenings 216 can be present. In some implementations, the openings canbe created by a chemical or laser etching, drilling, or milling processin which material is removed from the surface of the substrate 206. Theshape of the openings can be circular, rectangular, or any other shapesuitable for introducing fluid into the openings (e.g., into the inletsof the infusate channel of FIG. 1A) or extracting fluid from theopenings (e.g., from the outlets of the waste-collecting channel of FIG.1A).

FIG. 2D shows a cross-sectional view of the substrate material 216,channel 206, and openings 230. Also shown in FIG. 2D are structuralsupports 212 coupled to the substrate 216. The structural supports 212are intended to reinforce the structural integrity of the channel 206and to prevent deformation of a membrane that will be added later in theprocess, so the structural supports 212 are preferably made from asubstantially rigid material such as a polymer or a metal. As shown inFIG. 2D, the structural supports can be aligned with the direction offluid flow in the channel 206 (see arrows 124 a and 126 a of FIG. 1A),in order to reduce interference with the flow of infusate orwaste-collecting fluid in the channel 206. In other implementations, thestructural supports 212 can occupy a substantial portion of the channel206. For example, the structural supports 212 can be made from a porousmaterial that allows fluid to flow through the channel 206. Thestructural supports 212 can be coupled to the substrate 216 by amechanical joint or by a medical grade adhesive suitable for use in afluid channel.

FIG. 2E shows a cross-sectional view of the substrate 216 configured asin FIG. 2D, with the addition of a membrane 210. The membrane 210 can beused as either of the membranes 108 a or 110 a of FIG. 1A. In someimplementations, the membrane 210 is selected to allow clearance ofparticles having a molecular weight smaller than about 60 kDa. Themembrane 210 is coupled to the structural supports 210 in order toprevent the membrane 210 from deforming under the pressure of the fluidflowing through the channel 206. The membrane 210 can be joined to thestructural supports 212 by a mechanical fastener or by an adhesive.

FIG. 2F shows the features of the infusate channel of FIG. 1A. Asdiscussed above, the elements shown in FIG. 2E can be used to formeither the infusate channel or the waste-collecting channel of FIG. 1A.Therefore, structure of FIG. 2F can be manufactured by repeating theprocess described in connection with FIGS. 2A-2E to produce a secondstructure. The structure of FIG. 2F is similar to the structure shown inFIG. 2E, but rotated 180 degrees such that the openings 230 of FIG. 2Fare opposed to the openings of FIG. 2E.

FIG. 2G shows a pair of substrate walls 217. The substrate walls areparallel to each other and define the side walls of a channel 202, whichcan be used as the blood flow channel of FIG. 1A. The channel 202 isopen on its top and bottom sides at this step in the process, but willeventually be defined by the membranes 210 as shown in FIG. 2H.

FIG. 2H shows the final step of the manufacturing process formanufacturing the device of FIG. 1A. The membranes 210 of the twoinstances of channel 206 (depicted in FIGS. 2E and 2F) are joined to thesubstrate walls 217 (depicted in FIG. 2G) to form the channel 202, whichis defined on its upper and lower walls by the membranes 210, and on itssides by the substrate walls 217 as shown in FIG. 2G. The substratewalls 217 are not visible in the cross-sectional view of FIG. 2H. Thechannel 202 can be used as the blood flow channel of FIG. 1A, while thechannels 206 can be used as the infusate channel and waste-collectingchannel.

FIG. 3 depicts a block diagram of a control system 300 that can be usedwith the devices of FIGS. 1A-1C. The control system 300 includes anelectronic processor 302 in communication with fluid pressure sensors304, fluid flow sensors 306, a blood introduction device 308, and aninfusate introduction device 310. Because the devices of FIGS. 1A-1C areintended for use in hemofiltration, promoting health of the patient'sblood as it flows through the blood flow channel is essential. Thecontrol system 300 can be used to ensure that the patient's bloodremains healthy.

Pressure sensors 304 and flow sensors 306 can be placed inside the bloodflow channel. In some implementations, the physical shape of the fluidpressure sensors 304 and the flow sensors 306 can be selected to reduceinterference with the flow of blood in the blood channel. For example,the pressure sensors 304 and the flow sensors 306 can have a small sizeor a hydrodynamic shape in order to promote laminar fluid flow. Duringoperation of the device, the pressure sensors 304 and the flow sensors306 can measure the pressure and flow characteristics in the blood flowchannel and can transmit the measurements to the processor 302. Thepressure sensors 304 and the flow sensors 306 can report measurementscontinuously, or at predetermined time intervals.

The processor 302 can determine whether the pressure and flow in theblood channel are suitable for maintaining blood health. The processor302 can compare the measurements taken by the pressure sensors 304 andthe flow sensors 306 to predetermined ranges that are deemed to be safefor blood. If the pressure or flow rate is outside of the acceptablerange, the processor can attempt to correct the problem by transmittingsignals to the blood introduction device 308 or the infusateintroduction device 310. For example, the processor can reduce the flowrate in the blood channel by triggering the blood introduction device308 (e.g., a pump) to decrease the amount of blood introduced at theinlet of the blood flow channels. The processor can also respond to anunacceptably high fluid pressure in the blood flow channel by triggeringthe infusate introduction device 310 to reduce the rate at whichinfusate is introduced at the inlets to the infusate channel. In anotherexample, the processor can trigger the infusate introduction device 308to increase the rate at which infusate is introduced (e.g., to increasethe amount of convective clearance of toxins in the blood). In someimplementations, the processor 302 can control the blood introductiondevice 308 and the infusate introduction device 310 to achieve a desiredhematocrit profile in the blood channel. For example, the processor 302can control the blood introduction device 308 and the infusateintroduction device 310 to maintain a constant hematocrit levelthroughout the blood channel. Alternatively, in some implementations,the processor 302 can control the blood introduction device 308 and theinfusate introduction device 310 to create a hematocrit profile thatvaries along the length of the blood channel.

FIG. 4 is a flow diagram of a method 400 for filtering liquid containingan analyte, according to an illustrative implementation. The method 400includes the steps of introducing a first liquid solution (step 402),introducing infusate (step 404), introducing waste-collecting fluid(step 406), and collecting the cleansed liquid (step 408). In step 402,a first liquid containing an analyte is introduced into an inlet of oneor more first channels. In some implementations, the fluid is blood thathas been extracted from a patient for filtration. The analyte can be anyundesirable substance, such as urea, uric acid, creatinine, or othertoxins or pathogens. The first channels can have a height in the rangeof about 50 microns to about 500 microns, a width in the range of about50 microns to about 900 microns, and a length in the range of about 3centimeters to about 20 centimeters. If blood is to be introduced intothe first channel, the first channel can include an anticoagulantcoating on its inner walls and can be configured to maintain wall shearrates in the range of about 300 inverse seconds to about 3000 inverseseconds.

The method 400 includes the step of introducing infusate into an inletof at least one second channel (step 404). The second channel iscomplementary to one or more of the first channels, and the infusate isintroduced into the second channel such that it flows in a directionperpendicular to the direction of the first liquid in the first channel.The second channel is separated from the one or more complementary firstchannels by a first permeable membrane, which allows some of theinfusate to be transported from the second channel into the firstchannel.

The method 400 includes the step of introducing waste-collecting fluidinto an inlet of at least one third channel (step 406). The thirdchannel is complementary to one or more of the first channels, and thethird channel is separated from the one or more complementary firstchannels by a second permeable membrane, which allows some of theanalyte to be transferred from the first channel to the third channel.In some implementations, introducing the first liquid (step 402),introducing the infusate (step 404), and introducing thewaste-collecting fluid (step 406) can occur simultaneously andcontinuously. The waste-collecting fluid can be introduced such that thepressure in the third channel is less than the pressure in the adjacentfirst channel, which can result in an outflow of fluid form the firstchannel to the third channel.

In some implementations, introducing the first liquid (step 402),introducing the infusate (step 404), and introducing thewaste-collecting fluid (step 406) can occur simultaneously andcontinuously. For example, the first liquid, infusate, andwaste-collecting fluid can be flowed continuously through theirrespective channels. Infusate is transported from the second channel tothe first channel through the first membrane. The infusion of infusateinto the first channel causes an outflow of fluid from the first channelto the third channel through the second membrane. Waste particles, suchas urea, uric acid, or creatinine, are also transported through thesecond membrane and into the third channel. The waste-collecting fluidin the third channel then carries the waste particles away from thefirst channel.

As discussed above, the first liquid can be blood that has beenextracted from a patient for cleansing. The volume of liquid in thefirst channel can be substantially constant along its length so as tomaintain substantially constant hematocrit in the blood. Blood healthcan also be preserved by maintaining laminar flow in the first channeland holding fluid shear rates in a range of about 300 to about 300inverse seconds.

The method 400 can also include the step of collecting cleansed liquidfrom an outlet of the one or more first channels (step 408). As theliquid is transported along the length of the first channel from theinlet to the outlet, some of the waste particles in the liquid areremoved from the first channel through the second membrane, as discussedabove. Therefore, when the liquid reaches the outlet of the firstchannel, it has a substantially smaller concentration of wasteparticles. If the fluid is blood that has been extracted from a patient,the filtered blood can be collected at the outlet of the first channeland can then be returned to the patient.

What is claimed is:
 1. A system, comprising: a plurality of layers ofmaterials forming a first channel and a second channel with aninterchannel flow barrier between a first side of the first channel andthe second channel, and a third channel adjacent to a second side of thefirst channel; and a control system comprising: at least one fluidpressure sensor to measure fluid pressure characteristics in the firstchannel; at least one fluid flow sensor to measure fluid flowcharacteristics in the first channel; and a processor in communicationwith the at least one fluid pressure sensor and the at least one fluidflow sensor and, responsive to one or more measurements received fromthe at least one fluid pressure sensor or the at least one fluid flowsensor, configured to control an amount of convective clearance of bloodflowed through the first channel by increasing a rate at which infusateis introduced into the second channel to cause a net infusion of fluidfrom the second channel into the first channel and to cause a netoutflow of fluid from the first channel into the third channel.
 2. Thesystem of claim 1, wherein the first channel, the second channel, andthe third channel extend parallel to one another.
 3. The system of claim1, further comprising a structural support within at least one of thefirst channel, the second channel, or the third channel, the structuralsupport configured to limit the deformation of at least one of the firstmembrane or the second membrane.
 4. The system of claim 3, wherein thestructural support comprises a porous mesh including at least onematerial selected from the group consisting of ceramic, carbon, andpolymer.
 5. The system of claim 3, wherein the structural supportcomprises a post or ridge placed within at least one of the firstchannel, the second channel, or the third channel.
 6. The system ofclaim 3, wherein the structural support has a length that is less than alength of at least one of the first channel, the second channel, or thethird channel.
 7. The system of claim 3, wherein the structural supportspans a width of at least one of the first channel, the second channel,or the third channel.
 8. The system of claim 1, wherein the microfluidicdevice is configured such that the volume of a fluid flowing through thefirst channel is substantially constant along its length.
 9. The systemof claim 1, further comprising a second interchannel flow barrierseparating the first channel from the third channel.
 10. The system ofclaim 9, wherein the second interchannel flow barrier comprises amembrane.
 11. The system of claim 9, wherein the second interchannelflow barrier has a pore size selected to allow clearance of particleswith a molecular weight of no more than about 60 kDa.
 12. The system ofclaim 1, wherein the microfluidic device is configured such that ahematocrit profile in the first channel is selectably controllable by anoperator of the device when blood is flowed through the first channel.13. The system of claim 1, wherein the microfluidic device is configuredsuch that hematocrit is substantially constant throughout the firstchannel when blood is transported through the first channel.
 14. Thesystem of claim 1, wherein the first channel is configured such thatfluid flow in the first channel is substantially laminar.
 15. The systemof claim 1, wherein the first channel is configured to maintain a wallshear rate in the range of 300-3000 inverse seconds when blood istransported through the first channel.
 16. The system of claim 1,further comprising an anticoagulant coating on at least one innersurface of the first channel.
 17. The system of claim 1, wherein thefirst channel has a height in the range of about 50 microns to about 500microns, a width in the range of about 50 microns to about 900 microns,and a length in the range of about 3 centimeters to about
 20. 18. Thesystem of claim 17, wherein the first interchannel flow barriercomprises a membrane.
 19. The system of claim 1, wherein the firstchannel is defined in part by a substantially planar substrate, and thesecond channel and the third channel are configured to allow fluid toflow in a direction perpendicular to the plane of the substrate.
 20. Thesystem of claim 19, wherein the substrate is formed from at least one ofpolystyrene, polycarbonate, polyimide, polysulfone, polyethersulfone,acrylic, cyclic olefin copolymer (COC), polycaprolactone (PCL),orpolydimethylsiloxane (PDMS).